The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.
Discovery of imatinib mesylate (IM) as the targeted BCR-ABL protein tyrosine kinase inhibitor (TKI) has resulted in its use as the frontline therapy for chronic myeloid leukemia (CML) across the world. Although high response rates are observed in CML patients who receive IM treatment, a significant number of patients develop resistance to IM. Resistance to IM in patients has been associated with a heterogeneous array of mechanisms of which point mutations within the ABL tyrosine kinase domain (TKD) are the frequently documented. The types and frequencies of mutations reported in different population studies have shown wide variability. We screened 125 Malaysian CML patients on IM therapy who showed either TKI refractory or resistance to IM to investigate the frequency and pattern of BCR-ABL kinase domain mutations among Malaysian CML patients undergoing IM therapy and to determine the clinical significance. Mutational screening using denaturing high performance liquid chromatography (dHPLC) followed by DNA sequencing was performed on 125 IM resistant Malaysian CML patients. Mutations were detected in 28 patients (22.4%). Fifteen different types of mutations (T315I, E255K, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation. The data generated from clinical and molecular parameters studied were correlated with the survival of CML patients. Patients with Y253H, M351T and E355G TKD mutations showed poorer prognosis compared to those without mutation. Interestingly, when the prognostic impact of the observed mutations was compared inter-individually, E355G and Y253H mutations were associated with more adverse prognosis and shorter survival (P=0.025 and 0.005 respectively) than T315I mutation. Results suggest that apart from those mutations occurring in the three crucial regions (catalytic domain, P-loop and activation-loop), other rare mutations also may have high impact in the development of resistance and adverse prognosis. Presence of mutations in different regions of BCR-ABL TKD leads to different levels of resistance and early detection of emerging mutant clones may help in decision making for alternative treatment. Serial monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatments in such CML patients.
We examined the donor factors that may affect the yield of peripheral blood stem cell (PBSC) mobilized from healthy donors. Pre-apheresis PB-CD34(+) cell count was the only factor that correlated with PBSC yield. Leukocyte count (LC) and monocyte count (MC) correlated with PB-CD34(+) cell. Male gender and PB-CD34(+) cell count of at least 87.1/μL and 69.8/μL on day-4 and -5 of G-CSF were associated with the ability to harvest at least 5×10(6)/kg CD34(+) cells after one apheresis. We concluded that gender and PB-CD34(+) cell count are important predictors of PBSC yield. LC and MC may serve as surrogate markers for estimating the PB-CD34(+) cell count.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potential curative option for many patients with hematological malignancies (HM). However, the high rate of transplantation-related mortality (TRM) restricted the use of standard myeloablative HSCT to a minority of young and fit patients. Over the past few years, it has become evident that the alloreactivity of the immunocompetent donor cells mediated anti-malignancy effects independent of the action of high dose chemoradiotherapy. The use of reduced intensity conditioning (RIC) regimens has allowed a graft-versus-malignancy (GvM) effect to be exploited in patients who were previously ineligible for HSCT on the grounds of age and comorbidity. Retrospective analysis showed that RIC has been associated with lower TRM but a higher relapse rate leading to similar intermediate term overall and progression-free survivals when compared to standard myeloablative HSCT. However, the long term antitumor effect of this approach is less well established. Prospective studies are ongoing to define which patients might most benefit from reduced toxicity stem cell transplant (RT-SCT) and which transplant protocols are suitable for the different types of HM. The advent of RT-SCT permits the delivery of a potentially curative GvM effect to the majority of patients with HM whose outcome with conventional chemotherapy would be dismal. Remaining challenges include development of effective strategies to reduce relapse rates by augmenting GvM effects without increasing toxicity.
Progress in our understanding of multiple myeloma and its treatment has resulted in a more tailored approach to patient management, with different therapeutics regimens for different patient populations. The decision to initiate therapy depends primarily on the presence of symptoms which has to balance the chance of tumor clearance and against the risks of treatment related mortality. Selection of appropriate initial treatment should be based primarily on patient's characteristics (biologic age, co-morbidities), the disease characteristics (tumor burden and genetic risk profile) and the expected toxicity profile of the different regimens. When treatment begins, in younger transplant eligible patients the goal is to achieve high quality responses with intensive therapies as the quality of response appears to be important surrogates for long-term outcome. In the majority of myeloma patients in whom intensive treatment is not an option due to advanced age and co-morbidities, treatment should emphasize on optimal disease control to obtain symptomatic relief and to maintain a satisfactory quality of life. The introduction of novel agents has substantially changed the treatment paradigm of this otherwise incurable disease. The utilization of these drugs has moved from relapse setting to the front line setting and has benefited all patient groups. Because of these rapid developments and many treatment options we need good quality clinical studies to guide clinical practice in the management of patients with multiple myeloma. This review presents an update on current concepts of diagnosis and treatment of patients with multiple myeloma and provides recommendations on tailored therapies with particular reference to the local practice. The information presented herein may be used by the health care providers caring for myeloma patients as a guideline to counsel patients to understand their disease and the treatment better.
The incidence of Non-Hodgkin's lymphomas (NHL) is rising worldwide and if not adequately treated carries a high mortality rate. The pattern and frequency of NHL vary in different populations and geographical regions. It has considerable biologic and clinical heterogeneity and a definitive diagnosis can be made only after histopathogical examination. The histology and the extent of the lymphoma are the major determinants of optimal therapeutic regimen and treatment outcome. Additionally, the overall treatment strategies should be tailored according to medical status and preference of the patient. A holistic approach provided by a multi-disciplinary team of health care professionals is the cornerstone of ensuring successful treatment outcome. Importantly, therapy should be expedited and where possible performed in experienced centers. Patients achieving remission would require long-term monitoring for disease recurrence and late effects of cytotoxic chemotherapy and radiotherapy. Hence, clinicians should have a fundamental understanding in the biology and the principles of treatment of NHL. This review provides an evidence-based and systematic approach in designing therapeutic strategies for individual patients with newly diagnosed and relapsed NHL focusing on the common types of NHL with particular reference to the current practice within the local settings. The role of standard and novel therapeutic modalities in treatment will be summarized.
Irreversible optic nerve dysfunction associated with central retinal vein occlusion (CRVO) is an unusual but important complication of Waldenstrom Macroglobulinemia (WM). Acute visual loss in CRVO is mainly due the severe macular oedema. However, ischaemic optic neuropathy needs to be considered in patients with CRVO when, (i) there is a relative afferent papillary defect and central scotoma, (ii) the visual acuity is not consistent with the retinal pathology, and (iii) the visual defects persisted despite resolution of macular oedema following treatment of the hyperviscosity state. The ischaemic type of CRVO is associated with a poor visual prognosis and the presenting visual acuity has a prognostic role. We report the first description of irreversible unilateral optic nerve damage associated with CRVO in a patient with WM.
Hodgkin's disease (HD) in association with pregnancy is rarely reported. Thus, the data in the management of pregnancy complicated by HD is limited. We report here the management of advanced HD in pregnancy that was treated successfully with chemotherapy.
Methods that allow expansion of myeloid dendritic cells (MDCs) from CD34(+) cells are potentially important for boosting anti-leukemic responses after cord blood (CB) hematopoietic stem cell transplantation (HSCT). We showed that the combination of early-acting cytokines FLT3-ligand (FL), stem cell factor (SCF), interleukin (IL)-3, and IL-6 supported the generation of CD11c(+)CD16() CD1a()/c() MDCs from CB CD34(+) cells or CB myeloid precursors. Early-acting cytokine-derived MDCs were maintained within the myeloid CD33(+)CD14()CD15() precursors with a mean of 4 x 10(6) cells generated from 1-4 x 10(4) CB CD34(+) cells or myeloid precursors after 2 weeks. After 8-12 days of culture the MDCs expressed higher levels of HLA-DR antigen but lower levels of CD40 and CD86 antigen, compared to adult blood MDCs. At this stage of differentiation, the early-acting cytokine-derived MDCs had acquired the ability to induce greater allogeneic T cell proliferation than monocytes or granulocytes derived from same culture. Early-acting cytokine-derived MDCs exposed to the cytokine cocktail (CC) comprising IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and prostaglandin E (PGE)-2, upregulated the surface co-stimulatory molecules CD40 and CD86 and enhanced allogeneic T cell proliferation, as is characteristic of MDCs maturation. The reliable production of MDCs from CB CD34(+) cells provides a novel way to study their lineage commitment pathway(s) and also a potential means of enriching CB with MDCs to improve prospects for DC immunotherapy following CB HSCT.
Intense myelofibrosis is rarely associated with de novo acute myeloid leukaemia (AML) except in acute megakaryoblastic leukaemia (AML-M7) where there is diffuse marrow fibrosis as a consequence of proliferation of neoplastic myeloid cells. AML associated with significant myelofibrosis developing both de novo or secondary to primary (idiopathic) myelofibrosis is characterised by a fulminant course and extremely poor prognosis, primarily due to treatment-resistant disease. The prognostic value of degree of marrow fibrosis in de novo AML has been poorly investigated. We describe a case of extensive myelofibrosis associated with acute erythroblastic leukaemia (AML-M6) that responded to induction therapy of the leukaemia.
Owing to the importance of dendritic cells (DC) in the induction and control of immunity, an understanding of their biology is central to the development of potent immunotherapies for cancer, chronic infections, autoimmune disease, and induction of transplantation tolerance. This review surveys the heterogeneity of DC with regards to their phenotype and developmental origin, and how they initiate, modify and regulate the immune response, with emphasis on their maturation, migration, antigen-presentation and interaction with T cells and other immune cells. Much of this knowledge is obtained through research on murine DC. Research on human DC has been hampered by limitations associated with in vitro assays and limited access to human tissues. New approaches on human DC research are required in order to develop novel strategies for the treatment of microbial infections, the control of graft rejection, and the improvement of DC-based immunotherapeutic protocols for autoimmunity, allergy, and cancer.
Haemophagocytic syndrome (HPS) should be included in the differential diagnosis of pyrexia of unknown origin (PUO). The hallmark of HPS is the accumulation of activated macrophages that engulf haematopoietic cells in the reticuloendothelial system. We describe a patient with unexplained fever in which a final diagnosis of HPS was established in a bone marrow study.
The presence of serum cold agglutinin can be the initial presentation of lymphoproliferative diseases. Conditions with persistent cold agglutinins are a spectrum of diseases that vary from benign lymphoproliferation of the "autoimmune-like chronic cold agglutinin disease" to malignant lymphoma. We report a case of a 72-year-old woman who presented with severe anaemia, hepatosplenomegaly and episodes of peripheral haemagglutination precipitated by cold exposure. The haemoglobin was 5.6 g/dL with a cold agglutinin titer of 1:256 at 4 degrees C and 1:8 at room temperature (30 degrees C). The cold agglutinin showed anti-I specificity and kappa light chain restriction. Peripheral blood showed atypical lymphoid cells with a B-cell immunophenotype. Immunoglobulin gene rearrangement study by polymerase chain reaction (PCR) showed an amplified band at 100 bp, consistent with a clonal proliferation of B-lymphocytes. We believe that our patient had cold antibody haemolytic anaemia as the initial presentation of a low-grade non-Hodgkin's lymphoma. The association of cold antibody haemolytic anaemia with low-grade B-cell lymphoma is unusual.
Activation of immunoregulatory T lymphocyte subsets has been observed in dengue viral infection, being more evident in dengue hemorrhagic fever (DHF) than in classical dengue fever (DF). There are, however, as yet no well-defined host markers to determine which patients with dengue viral infection will develop severe complications during the acute febrile stage of the disease. A study was performed to compare the cellular immune status in DHF, DF and non-dengue viral infections (NDF) in order to determine the value of these parameters in distinguishing DHF from classic DF and other viral infections during the acute febrile stage of the disease. This study involved 109 febrile patients admitted because of suspected DHF. Fifty patients were serologically confirmed cases of dengue infection, of which 25 had grade 1 or 2 DHF. There was a reduction in total T (CD3), CD4 and CD8 cells in DHF and demonstrated that a low level of CD3, CD4, CD8 and CD5 cells discriminated DHF from DF patients during the febrile stage of the illness. In contrast, B (CD19) cells and natural killer (NK) cells did not appear to be discriminatory in this study. Receiver operating characteristic (ROC) curve analysis showed that a combination of CD3 cell of < or = 45% and CD5 cell of < or = 55% was the best marker to identify DHF patients (sensitivity = 84% and specificity = 52% for CD3 cell of < or = 45%; sensitivity = 92% and specificity = 71% for CD5 cell of < or = 55%). CD4 cell of < or = 25% and CD8 cell < or = 30% were equally good in discriminating DHF from DF patients. On the other hand, the ROC curves indicated no clear difference between the immunoregulatory cell counts in DF from NDF Lymphopenia, atypical lymphocytosis and thrombocytopenia were significantly more evident in dengue compared to non-dengue infection but did not appear to be discriminatory among DHF and DF patients. The reduction in CD3, CD4, CD8, CD5 cells correlated with the degree of thrombocytopenia in DHF (p < 0.05) which suggests that these cells probably participate in a common pathogenetic mechanism.
Leukemic infiltration of the optic nerve is rare [1]. [Camera, A., Piccirillo, G., Tranfa, F., Rosa, N., Frigeri, F., Martinelli, V., Rotoloi, B. (1993) "Optic nerve involvement in acute lymphoblastic leukemia", Leuk. Lymph. 11, 153-155]. Radiotherapy should be given urgently to all patients with optic nerve infiltrate to restore their vision [2]. [Rosenthal, A. (1983) "Ocular manifestation of leukemia", Ophthalmology 90, 899-905]. We report a case of a unilateral optic nerve relapse 7 months after diagnosis of acute lymphoblastic leukemia (ALL) in a 17-year-old boy who had been off treatment for 6 weeks. The ocular symptoms was initially diagnosed as primary optic neuritis and treated with corticosteroids resulting in temporary clinical recovery. Radiation therapy for ocular leukemia that was commenced 2 months after the onset of symptoms failed to reverse the visual loss. The lack of a reliable and effective tool to diagnose ocular leukemia at an early stage has resulted in significant treatment delay and poor visual outcome.
Nocardia infection is rare in bone marrow transplant (BMT) recipients with less than 30 cases reported in the literature [1-4]. The majority of the cases occurred late in the post-transplant period. Common clinical presentations included formation of widespread and multiple abscesses. Bone marrow hypoplasia is an uncommon finding. We describe the first case of nocardiosis, diagnosed at day 100 after non-myeloablative allogeneic peripheral blood stem cell transplantation, presenting as pancytopenia and hypocellular marrow. Eradication of the infection with antibiotics resulted in complete hematological recovery.